Transcript Document 7301408

Metabolism of lipids
Course Content
•Digestion and absorption of lipids
•Triacylglycerol metabolism
•Phospholipid metabolism
•Cholesterol metabolism
•plasma lipoprotein metabolism
Summary
•Definition
• Classes
fats
lipids
: triacylglycerols, TG
cholesterol, Ch
cholesteryl ester, CE
lipoids phospholipids, PL
glucolipids, GL
• Function
nomenclature
Fatty acids：
Saturated fatty acids
14〜20C palmitic acid
16C stearic acid 18C
Unsaturated fatty acids
Linolenic acid 18C three unsaturated bonds
Linoleate 18C two unsaturated bonds
Arachidonic acid 20C four unsaturated bonds
Essential fatty acids
required for the growth of mammals and they must be
obtained from food. Including linoleate 、 linolenate,
arachidonic acid amount unsaturated in plant
Section I
Digestion and absorption of lipids
• digestion：
– small intestine：bile、pancreatic lipase、colipase、
phospholipase A2、 cholesteryl esterase
– product：2-monoacylglycerol(MG)、FFA、
Cholesterol、lysophospholipid
• absorption
Chemical Structure of Triacylglycerol
Fatty Acid Synthesis
• Palmitic acid synthesis
• Elongation of FA carbon-chainER
– ER
--Mitochondrial
• Synthesis of Unsaturated FA
• Regulation of unsaturated FA
Biosynthesis of palmitic Acid
• Tissues：liver(major site) 、kidney、
breast、adipose、 lung 、 brain
---Cytosol
• Materials：Acetyl-CoA、NADPH+H+、ATP、
HCO3- and Mn2+
• Pathway
---Synthesis of malonyl-CoA
---Synthesis of fatty acid
Citrate Pyruvate Cycle
malonyl-CoA Synthesis
限速酶
ÒÒ
õ£CoAôÈ»¯Ã¸
CH3COSCoA £«HCO3- £«ATP
ÉúÎï ËØ¡¢Mn
2+
HOOCCH2COSCoA£«ADP£«Pi
±û¶þõ£CoA
ÄûÃÊËá¡¢ ÒìÄûÃÊËá
ÒÒ
õ£CoAôÈ»¯Ã¸£º
Pi
(+)
ÒȵºËØ
µ°°×Á×Ëáø
H2O
µ¥Ìå
(ÎÞ »î ÐÔ
)
¶à¾Û
Ìå
³¤ Á´Ö¬õ£CoA (Óлî ÐÔ
)
ÒÒ
õ£CoAôÈ»¯Ã¸
£¨ Óлî ÐÔ
£©
ÒÒ
õ£CoAôÈ»¯Ã¸
£¨ ÎÞ»î ÐÔ
£©
ATP
µ°°×¼¤Ã¸
P
ADP
(+)
ÒȨ̀ßѪÌÇËØ
Enzyme-biotin
HCO3 + ATP
1
ADP + Pi
Enzyme-biotin-CO2
O
ll
CH3-C-SCoA
acetyl-CoA
2
Enzyme-biotin
O
-
ll
O2C-CH2-C-SCoA
malonyl-CoA
The overall reaction, which is spontaneous, may be
summarized as:
HCO3- + ATP + acetyl-CoA  ADP + Pi + malonyl-CoA
Acetyl-CoA Carboxylase, which converts acetyl-CoA to
malonyl-CoA, is the committed step of the fatty acid
synthesis pathway.
The mammalian enzyme is regulated, by
 phosphorylation
 allosteric control by local metabolites.
Conformational changes associated with regulation:
 In the active conformation, Acetyl-CoA Carboxylase
associates to form multimeric filamentous complexes.
 Transition to the inactive conformation is associated
with dissociation to yield the monomeric form of the
enzyme (protomer).
Phosphorylated protomer of
Acetyl-CoA Carboxylase (inactive)
Citrate
AMP-Activated
Kinase catalyzes
phosphorylation
of Acetyl-CoA
Carboxylase,
causing
inhibition.
Dephosphorylated,
e.g., by insulinactivated Protein
Phosphatase
Palmitoyl-CoA
Phosphorylated, e.g., via
AMP-activated Kinase
when cellular stress or
exercise depletes ATP.
Dephosphorylated Polymer of
Acetyl-CoA Carboxylase (active)
Regulation of Acetyl-CoA Carboxylase
The decreased production of malonyl-CoA prevents
energy-utilizing fatty acid synthesis when cellular energy
stores are depleted. (AMP is abundant only when ATP has
been extensively dephosphorylated.)
Phosphorylated protomer of
Acetyl-CoA Carboxylase (inactive)
Citrate
Dephosphorylated,
e.g., by insulinactivated Protein
Phosphatase
Palmitoyl-CoA
Phosphorylated, e.g., via
AMP-activated Kinase
when cellular stress or
exercise depletes ATP.
Dephosphorylated Polymer of
Acetyl-CoA Carboxylase (active)
Regulation of Acetyl-CoA Carboxylase
The antagonistic effect of insulin, produced when
blood glucose is high, is attributed to activation of
Protein Phosphatase.
Phosphorylated protomer of
Acetyl-CoA Carboxylase (inactive)
Citrate
Regulation of
Acetyl-CoA
Carboxylase by
local metabolites:
Dephosphorylated,
e.g., by insulinactivated Protein
Phosphatase
Palmitoyl-CoA
Phosphorylated, e.g., via
AMP-activated Kinase
when cellular stress or
exercise depletes ATP.
Dephosphorylated Polymer of
Acetyl-CoA Carboxylase (active)
Regulation of Acetyl-CoA Carboxylase
Palmitoyl-CoA (product of Fatty Acid Synthase) promotes
the inactive conformation, diminishing production of
malonyl-CoA, the precursor of fatty acid synthesis.
This is an example of feedback inhibition.
Glucose-6-phosphatase
glucose-6-P
glucose
Gluconeogenesis
Glycolysis
pyruvate
fatty acids
acetyl CoA
Citrate
allosterically
activates AcetylCoA Carboxylase.
ketone bodies
cholesterol
citrate
oxaloacetate
Krebs Cycle
[Citrate] is high when there is adequate acetyl-CoA
entering Krebs Cycle.
Excess acetyl-CoA is then converted via malonyl-CoA to
fatty acids for storage.
Fatty acid synthesis from acetyl-CoA & malonyl-CoA
occurs by a series of reactions that are:
 in bacteria catalyzed by 6 different enzymes plus a
separate acyl carrier protein (ACP)
 in mammals catalyzed by individual domains of a very
large polypeptide that includes an ACP domain.
NADPH serves as electron donor in the two reactions
involving substrate reduction.
The NADPH is produced mainly by the Pentose Phosphate
Pathway.
Mammalian fatty acid
synthase
• A dimer of two polypeptides of 240 kDa each
• Each polypeptide contains eight domains that
represent the seven catalytic centres plus an
integral acyl carrier protein (ACP) domain
4′ phosphopantetheine
The structure of the mammalian Fatty Acid Synthase protein is
summarized above
KS = b-Ketoacyl Synthase (Condensing Enzyme)---(Cys)
AT =Acyl transferase
MT = Malonyl/Acetyl-CoA Transacylase
DH = Dehydratase
ER = Enoyl Reductase
KR = b-Ketoacyl Reductase
TE = Thioesterase
ACP = Acyl Carrier Protein ---(Pant)
4. Reduction
5. Acyl transfer
3.Dehydration
2.Reduction
1.Condensation
• Elongation of FA Carbon-chain
– ER
– Mitochondria
• Synthesis of unsaturated FA
– unsaturated FA ：软油酸、Oleate、linoleate、
linolenate、arachidonic acid （ Essential FA ）
– Essential FA：required for the growth of mammals
and they must be obtained from food. Including
linoleate、linolenate, arachidonic acid
Regulation of FA synthesis
– Dietary factors: carbohydrate promotes
synthesis
– Hormone factors
insulin，“store hormone”，increase FA
synthesis
Glucagon ，“release hormon”，inhibit FA
synthesis
Important of polyunsaturated fatty acids---prostaglandins
(PG)、 thromboxanes (TX)、 leukotrienes (LT)
• Chemical structure and nomenclature
of PG、
TX、 LT
• Synthesis of PG、TX and LT
• Physiological functions of PG、TX and LT
O
OH
O
O
R1
R1
R1
R1
R2
R2
R2
R2
B
A
O
C
D
OH
O
R1
R1
R1
O
R2
R2
R2
OH
O
OH
E
G
F
COOH
O
R1
O
R2
R2
O
OH
H
H
I
COOH
O
CH 3
O
OH
Thromboxane A2
11
9
7
O 5
3
12
13
14
15
17
19
CH 3
20
Leukotriene A4(LTA4)
1
COOH
Synthesis of Triglycerides
location：liver、adipose tissue and small
intestinal
materials：glucose、dietary fats
pathway：Acylglycerol pathway
diacylglycerol pathway
Degradation of Triacylglycerols
• Lipolysis
• Glycerol Metabolism
• β-Oxidation
• Other oxydation modes
of fatty acid
• Formation and utilization of Ketone
Bodies
Lipolysis
• Concept
• Committed enzyme：hormone-sensitive
triglyceride
lipase (HSL)
• Lipolysis hormones：adrenalin 、glucagon、
ACTH and TSH
• Anti-lipolysis hormones：Insulin、PEGE2 and
Nicotinic Acid
PP
i
AD
P
HSL
HSL
(inactive)
(active)
Pi
P
Glycerol metabolism
Experimental evidence for β-Oxidation of fatty acid
̼±½Ö¬Ëá
ż
̼±½Ö¬Ëá
Ææ
CH 2CH 2CH 2CH 2CH 2COOH
CH 2CH 2CH 2CH 2COOH
CH 2CH 2CH 2COOH
CH 2CH 2COOH
CH 2COOH
COOH
O
CH 2C NHCH 2COOH
ÄòËá
±½ÒÒ
ËáÑÜÉúÎï )
(±½ÒÒ
O
C NHCH 2COOH
ÂíÄòËá
(±½¼×ËáÑÜÉúÎï )
β-Oxidation
of fatty acid
• 概念：脂肪酸氧化从羧基端β-碳原子开始，每次
释放出一个二碳片段（acetyl-CoA）
• Steps：Activation of FAenter into mitochondria
β-oxidation
TAC(Tricarboxylic acid cycle)
Activation of fatty acid —
Formation of Acyl-CoA
• Location：cytosol
O
RC OH + HSCoA
acyl-CoA
Carnitine
(Acyl-CoA)
(Carnitine)
Mitochondrion
Carnitine
acyltransferase Ⅰ
CoAS
H
Carnitine
acyltransferase Ⅱ
CoAS
H
限速酶
β-Oxidation of fatty acid
• location：mitochondrial matrix
• 过程：在脂肪酸β-氧化多酶复合体的催化下，
从脂酰基β碳原子开始，dehydrogenation 、加水
hydration、dehydrogenation
、thiolysis四步，生成一分子
比原来少两个碳原子的脂酰CoA(acyl-CoA)及一
分子乙酰CoA(acetyl-CoA)
β α
FAD
(dehydrogenation)
FADH
H2
O
(hydration)
NAD+
(dehydrogenation)
NADH
CoASH
H
+
(thiolysis)
O
Ö¬·¾Ëá
RCH2CH2C
Ö¬õ£CoA
ºÏ ³Éø
OH
ATP+HSCoA
AMP+PPi
O
Ö¬õ£CoA
RCH2CH2C ¡« SCoA
C
O
Ïß Á£Ìå ÄÚĤ
Ö¬õ£CoA
RCH2CH2C ¡« SCoA
FAD
2¡« P
Ö¬õ£CoAÍÑÇâø
FADH2
H2O
ºôÎü
Á´
O
·´ ¦¤2£-Ï©Ö¬õ£CoA ¦Â ¦Á
RCH CHC ¡« SCoA
2
¦¤ £- Ï©Ö¬õ£CoA
H2O
Ë®»¯Ã¸
OH
O
¦Â ¦Á
L(+)¦Â£-ôÇÖ¬õ£CoA RCH CH2C ¡«+SCoA
L(+)¦Â£- ôÇÖ¬õ£ NAD
NADH+H+
CoAÍÑÇâø
O
O
¦Â ¦Á
RC CH2C ¡« SCoA
¦Â£-ͪ Ö¬õ£CoA
¦Â£- ͪ Ö¬õ£CoA
Áò½âø
O
¢ÙÍÑÇâ (dehydrogenation)
¢Ú¼Ó
Ë®(hydration)
3¡« P
ºôÎü Á´
H2O
¢ÛÍÑÇâ(dehydrogenation)
¢ÜÁò½â(thiolysis)
HSCoA
O
Ö¬õ£CoA RC ¡« SCoA + CH3C ¡« SCoA
(ÉÙÁ½
¸ö̼Ô-×Ó)
ÒÒ
õ£CoA
脂肪酸β-Oxidation要点
• 脂肪酸仅需活化一次（cytosol），消耗一个
ATP的两个高能键；
• Acyl-CoA由carnitine运入线粒体，限速酶：
CAT-Ⅰ；
• β-Oxidation（mitochondrion）: including
dehydrogenation
、hydration 、dehydrogenation 、
thiolysis four repeated steps
脂肪酸氧化的能量生成
• 如软脂酸（C16）：
– 7次β-氧化，生成8分子乙酰CoA、7分子
FADH2及7分子NADH
即 12 ×8 +2×7+3 ×7=131分子ATP
– 脂肪酸活化时消耗2个高能磷酸键
– 净生成131-2=129分子ATP
n
n
• formula：12 × 2 +5 ×(2 -1) –2
• 能量利用率：51.6 ¡Á129
¡Á100=68%
9791
Difference between synthesis and
degradation of palmitic Acid
difference
synthesis
degradation
cytosol
mitochondria
ACP
CoA
Two carbonfragment
reducing
equivalents
HCO3- and citrate
Malonyl-CoA
Acytel-CoA
NADPH
FAD、NAD+
needed
Not needed
Energy alteration
Consume 7ATP＋
14NADPH
Form 129ATP
location
Acyl carrier
Difference Between Fatty Acid Synthesis And
β-Oxidation
Diffference
Location
Thioester linkage
Two carbonfragment
Electron carrier
HCO3- and
cytratre
Energy alteration
Synthesis
β -Oxidation
Cytoplasm
Mitochondrion
ACP
CoA
Malonyl-CoA
Acetyl-CoA
NADPH
FADH、NADH
needed
Nod needed
Consume 7ATP＋
14NADPH
Form 129ATP
Other oxydation modes
of fatty acid
• Oxydation of unsaturated FA
• FA oxydation in peroxisomes
• Oxydation of propionic acid
Formation and utilization of Ketone Bodies
• Ketone Bodies：Acetoacetate、 βHydroxybutyrate and Acetone
• Ketogenesis
• Utilization of Ketone Bodies
• Physiology Significance of Ketogenesis
• Regulation of Ketogenesis
ketone bodies(KB)
γ
Acetoacetate
β
α
β-hydroxybutyrate
Acetone
CoASH
CoASH
限速酶
CoASH
βα
NAD+
CO2
NAD
H
H+
Utilization of Ketone Bodies
HSCoA+ATP
ÒÒ
õ£ÒÒ
õ£Áò¼¤Ã¸
AMP+PPi
CH2COCH2COOH
ÒÒ
õ£ÒÒ
Ëá
CH3COCH2COSCoA
ÒÒ
õ£ÒÒ
õ£CoAÁò½âø
COOH
CH 2
COSCoA
çúçêõ£CoAתÁòø
CH 2
COOH
CH 2
COOH
HSCoA
2CH3COSCoA
±ûͪ
CH 2
TCAÑ-»·
ÌÇÒìÉú
±ûͪ Ëᣨ»òÈéËᣩ
ÌÇ
Liver
Blood
Extrahepatic Tissues
①
②
Urine
⑥
③
Citric
acid
cycle
④
⑤
Acetone
Lungs
⑦
Citric
acid
cycle
Major energy materials
provided for tissues
Glucose
Red Blood
Cell
+
Brain
+
Muscle
Liver
FFA
KB
+
+(exercise)
+(rest)
+
+
+
Concentration of energy materials of the blood in
full of eating or hungry (mmol/L)
Glucose
β-Hydroxybutyrate
Acetoacetate
Full(of eating)
Hungry(5-6 weeks)
5.0
4.49
0.02
6.67
1.17
Three Crucial Steps for Ketogenesis Regulation
• Control of free fatty acid(FFA) mobilization
from adipose tissue
• The activity of carnitine acyltransferase
(CAT-1) in liver,which determines the
propotion of the fatty acid flux that is
oxidized rather than esterified;
• Partition of acetyl-CoA between the
pathway of ketogenesis and the citric acid
cycle
复习题
• 名词解释
– 1、脂肪的动员(lipolysis)；
– 2、激素敏感性甘油三酯脂肪酶(HSL)；
– 3、脂解激素；
– 4、脂肪酸的β-氧化(β-oxidation)；
– 5、必需脂酸(essential fatty acid)；
– 6、酮体(ketone bodies)
• 问答
– 1、简述胆汁酸盐的生理作用。
– 2、简述酮体生成的生理意义。
– 3、写出甘油异生为葡萄糖的过程。
– 4、一分子三软脂酰甘油彻底氧化成CO2 和
H2O，产生多少分子ATP？写出代谢途径的
全过程。
测试题
• 1、胆汁酸盐在 脂 类 消 化 中 主 要 作 用：
A、 有 使 脂 肪 乳 化 的 作 用
B、 有 促 进 脂 肪 吸 收 的 作 用
C、 有 促 进 胰 脂 酶 活 性 的 作 用
D、 使 水 解 的 脂 类 呈 溶 解 状 态
E、 有 促 进 辅 脂 酶 活 性 的 作 用
(A、B)
测试题
• 2、参 与 脂 肪 酸 氧 化， 以 FAD 为 辅
基的酶催化:
(D)
A、 还 原 不 饱 和 脂 酰 CoA
B、 β-羟 脂 酰 CoA 脱 氢
C、 脂 肪 酸 的 激 活
D、 脂 酰 CoA 脱 氢
E、 β-酮 脂 酰 还 原
测试题
• 3、一分子14 碳的肉豆蔻酸经β-氧化为乙酰CoA
A、活化肉豆蔻酸消耗2 分子高能磷酸键
B、肉豆蔻酸需经7次β-氧化才生成7分子乙酰CoA
C、生成6 分子FADH2 和6 分子NADH + H+
D、肉毒碱脂酰转移酶Ⅱ是豆蔻酸β-氧化的关键酶
(A、C)
测试题
• 4、对脂酸分解代谢而言下列哪一种叙述是错误的？
A、存在于胞液
B、生成CH3CO~CoA
C、β氧化的活性形式是RCH2CH2CH2CO~CoA
D、一种中间物是RCH2CHOHCH2CO~CoA
E、反应进行时NAD+→NADH
(A)
测试题
• 5、彻底氧化1分子硬脂酰CoA（18：0）
共需消耗多少分子O2？
A、23
B、26
C、30
D、16
E、32
(B)
测试题
• 6、有关酮体的正确叙述是：(A、B、C、D)
A、酮体包括丙酮、乙酰乙酸和β-羟丁酸
B、酮体可以从尿中排出
C、饥饿可引起酮体增加
D、糖尿病可引起酮体增加
测试题
• 7、能将酮体氧化成CO2和H2O的组织是
A、心肌
B、红细胞
C、脑
D、肝
(A、C)
本小节要求
•掌握软脂酸合成的原料、限速酶；了解软
脂酸合成过程及合成的调节。
•熟悉前列腺素、血栓噁烷及白三烯合成的
原料。
Section II
Phospholipid Metabolism
Classification of Phospholipids
•phosphoglyceride
Phosphatidylcholine (PC)
Phosphatidylethanolamine (PE)
Phosphatidylserine (PS)
Phosphatidylglycerol (PG)
Diphosphatidylglycerol (DPG)
phosphatidyl inositol(PI)
•Sphingomyelin
Chemical Structure of Phosphoglyceride
O
O
R2 C
CH 2 O
O CH
CH 2 O
C
R1
O
P
O
X
O-
Most phospholipids have a saturated fatty acid on C-1
and an unsaturated fatty acid (Arachidonic Acid )on C2 of the glycerol backbone.
Structure of Phospholipid
Classification of phosphoglyceride-1
• X-OH
X-
name
Classification of phosphoglyceride-2
X-OH
X-
name
Glycerophospholipid synthesis
• Site: liver，kidney，intestine
– endoplasmic reticulum, ER
• Sources：FA，glycerol，phosphate，nitrogenous
base （choline，ethanolamine，serine，inostol,etc），
ATP, CTP
• CDP- nitrogenous base
• CDP-diacylglycerol
CDP-choline与CDP- diacylglycerol
Diacylglycerol Pathway
O
CH 2OH
ÆÏÌÑÌÇ
HO
CH 2O
תõ£Ã¸
HO
CH
CH 2O
P
R1COCoA
3-Á×Ëá¸ÊÓÍ
R1
CH
CH 2O
CoA
C
P
1-Ö¬õ£-3-Á×Ëá¸ÊÓÍ
O
O
תõ£Ã¸
CH 2O
C
R1
Á×Ö¬ËáÁ×Ëáø
R2 C O CH
R2COCoA
CoA
CH 2O
Pi
P
Á×Ö¬Ëá
O
O
O
CH 2O
C
R1
תõ£Ã¸
R1 C
R2 C O CH
CH 2OH
1,2-¸ÊÓͶþõ¥
£¨ DG£©
O
R3COCoA
CoA
CH 2 O
O CH
CH 2 O
¸ÊÓÍÈýõ¥
£¨ TG£©
C
R2
O
C
R3
Diacylglycerol Pathway—PE, PC
CDP- Diacylglycerol Pathway—PI、PS、DPG
Synthesis of CDP- nitrogenous
base
Phosphoglycerol degradation
Synthesis and Degradation
of Sphingomyelin
•Site: brain---ER
•Souces:palmitoyl-CoA,
Serine,NADPH+H,FAD
•Pathway:
Degradation of Sphingomyelin
• Sphingomyelinase (PLC )
-----Defects in the enzymes result in
genetic diseases such as NiemannPick disease
本小节要求
• 熟悉常见甘油磷脂的名称、组成、合成
原料及CTP的作用；了解各种磷脂酶作
用的部位。
作业题
• 1、以下两题任选一题（必做）
– 吃的多动的少容易长胖，试从生化角度分析其
原因。
– 从生化角度谈谈你对减肥的认识。
• 2、请用代谢图将糖类与脂类的合成与分解
代谢联系起来。（必做）
• 3、简述甘油磷脂合成的原料及辅助因子。
• 4、葡萄糖如何为脂酸合成提供原料？
测试题
• 彻底氧化1分子硬脂酰CoA（18：0）共
需消耗多少分子O2？
A、23
B、26
C、30
D、16
E、32
(B)
复习题
• 1、关于脂酸生物合成的途径正确的是：
A、不需乙酰CoA
B、中间产物是丙二酰CoA
C、在线粒体内进行
D、以NADH为还原剂
E、最终产物为十碳以下脂酸
(B)
复习题
• 2、脂酸合成所需的乙酰CoA由
A、胞浆直接提供
B、线粒体合成并转化为柠檬酸转运
到胞浆
C、胞浆的乙酰肉毒碱提供
D、线粒体合成，以乙酰CoA的形式
E、胞浆的乙酰磷酸提供 (B)
复习题
• 3、下列磷脂中哪一个含有胆碱？
A、脑磷脂 B、卵磷脂
C、磷脂酸 D、心磷脂
(B)
复习题
• 4、合成卵磷脂时所需的活性胆碱是
A、TDP-胆碱 B、ADP-胆碱
C、UDP-胆碱 D、GDP-胆碱
E、CDP-胆碱
(E)
Section IV
Cholesterol(Ch) Metabolism
Cholesterol Structure
RCOO
HO
Cholesterol(Ch)
Cholesterol Ester(CE)
环戊烷多氢菲
Roles of Cholesterol
• Membrane component
• Steroid synthesis
• Bile acid/salt precursor
• Vitamin D precursor
Sources of Cholesterol
Diet
De novo synthesis
Cholesterol synthesized
in extrahepatic tissues
Liver cholesterol
pool
Secretion of HDL
and VLDL
Free cholesterol
In bile
Conversion to bile salts/acids
Dietary Cholesterol
•
•
•
•
Animal products – eggs
Absorb about 50%
Increase intake = decreased absorption
Excrete – 1 g/day (bile acids)
Dietary Cholesterol
•
•
•
•
Assume 400 mg intake / day
200 mg is absorbed
1000 mg is excreted
800 mg from de novo synthesis
Lowering cholesterol in diet has very little
effect on blood cholesterol !!!
Cholesterol Synthesis
• 80 % in liver, ~10% intestine, ~5% skin
Occurs in cytosol
• Requires 18Acetyl-CoA、16NADPH、36ATP
• Similar to ketogenic pathway
Highly regulated
Cholesterol Synthesis-1
2 CH3COSCoA
硫解酶
CH3COCH2COSCoA
CH3COSCoA
HMGCoA合成酶
CH3
HOOCCH2C CH2COSCoA
HMGCoA
OH
NADPH+H
限速酶
HMGCoA还原酶
+
CoA + NADP
CH3
HOOCCH2C CH2CH2OH
OH
甲羟戊酸
（MVA，C6 ）
Cholesterol Synthesis -2
OH
OH
MVA
P
H OCH2CH2CCH2COOH
P
OCH2CH2CCH2COOH
CH3
CH3
P
P
OCH2CH2C
CH2
异戊烯焦磷酸
(IPP，C5)
CH3
P
胆固醇( C2 7) ?
HO
P
OCH2CH
（3 ×）
P
P
头
羊毛固醇
头
( C3 0)
头
头
鲨烯( C3 0)
C
CH3
二甲丙烯焦磷酸
(DPP，C5)
CH3
焦磷酸法尼酯
(FPP，C15)
O
O
P
P
O
P
P
Cholesterol Synthesis
Summary
HMG CoA reductase Phosphorylation
HMG CoA reductase – OH
(active)
HMG CoA reductase – P
(inactive)
AMP-Activated
Protein Kinase (high activity)
(+)
phosphatase
AMP
(+)
(+)
Insulin
kinase
AMP-Activated
Protein Kinase
(low activity)
increase cAMP
Glucagon/epi
Conversion of Cholesterol
• Bile acid: liver (2/5)
• Steroids: adrenal cortex, testicle,ovary
• Vitamin D: skin(7-dehydrocholeterol and
Vitamin D3)
本小节要求
• 掌握胆固醇结构特点、合成原料、限速酶；
了解其合成过程；熟悉胆固醇的转化产物。
• 熟悉各种血脂的分类、组成特点；掌握其
功能；了解载脂蛋白的功能；
Section IV
Metabolism of Plasma
Lipoproteins
•Plasma lipids
•Plasma lipoproteins
•Apolipoproteins
• Metabolism of Plasma Lipoproteins
• Medical implications
Plasma Lipids ----Lipids in plasma
– TG：100mg/dl
– PL： 200mg /dl
lecithins
70%
nerve sphingomyelin 20%
cephalin
10%
– Ch and CE：200mg /dl
Ch:55mg /dl;
CE:145mg /dl
– FFA：15mg /dl
Origin of plasma lipids：
Exogenous: dietary lipids
Endogenous: synthetized by liver, adipose tissue and
other tissues
Plasma Lipoproteins
Classes：
– electrophoresis：CM (Chylomicron) 、β、 pro-β、α
– ultracentrifugation：
CM、VLDL(very low density lipoprotein)、LDL、HDL
Compositions of plasma lipoproteins
CM
VLDL
0.950
LDL
1.006 1.019
IDL
HDL
1.063
1.125
HDL2
1.210
HDL3
CM
VLDL
d=80-500nm
Pr=0.5-2%
TG=80-95%
PL=5-7%
C=1-4%
apoA
apoB48
apoC
LDL
HDL
d=25-80
d=20-25
d=7.5-10
Pr=5-10%
Pr=20-25%
TG=50-70%
PL=15%
C=15%
TG=10%
PL=20%
C=45-50%
apoB100
apoE
Pr=50%
TG=5%
PL=25%
C=20%
apoB100
apoC
apoE
apoAⅠ
apoAⅡ
apoC
apoE
apoD
Apolipoproteins (apo) -1
Type
Association
Function
B48
Chylomicron
Carry cholesterol esters
Lacks LDL recpt
binding domain
B100
VLDL,IDL,LDL
Binds LDL recpt.
C-II
Chyl. VLDL, IDL, HDL
Activates LPL
C-III
Chyl. VLDL, IDL, HDL
Inhibits LPL
E
Chyl. Remnant, VLDL, IDL
HDL
Binds LDL recpt
A-1
HDL/Chylomicron
AⅡ
AⅣ
HDL
HDL,CM
LCAT activator
(lecithin:cholesterol
acyltransferase)
HL(+)；稳定HDL
LPL(+)
Apolipoprotein (apo) -2
Type
Association
Function
D
HDL
transports CE
J
HDL
binds and transports lipids
CETP
HDL
transports CE,TG
PTP
HDL
transports PL
Major Enzymes for Lipoprotein
Metabolism
• lipoprotein lipase,LPL
• hepatic lipase,HL
• lecithin: cholesterol acyltransferase, LCAT
• acyl-CoA: cholesterol acyltransferase, ACAT
• lipoprotein lipase，LPL
O
R2
C
O
O
CH2 O C R1
C H
O
CH2 O C R3
TG
DG
FFA
• hepatic lipase，HP
glycerol
MG
FFA
FFA
lecithin: cholesterol acyltransferase, LCAT
O
R2 C O
O
CH2 O C R1
C H O
CH3
CH2 O P O CH2 CH2 N+ CH3
CH3
OH
O
HO
OH
LCAT
R2COO
HO
CH2 O C R1
C H O
CH2 O P O CH2 CH2
CH3
N+ CH3
CH3
acyl-CoA: cholesterol acyltransferase,ACAT
RCOSCoA
CoA
ACAT
HO
RC O O
CM Metabolism
食物
TG
新生CM
apoCⅡ激活LPL
B48
TG
C,PL
A
成熟CM
小肠
apoC,E
A
TG
C,PL
C
E
C
A PL
C E
HDL
Ch
肝
FFA
B48
脂蛋白脂肪酶
apoA,C
B48
apoE
受体
FFA
TG
C,PL
E
CM残粒
肝外组织
甘油
VLDL Metabolism
新生
VLDL
apoCⅡ激活LPL
B100
TG
C,PL
成熟
VLDL
apoC,E
C
A PL
C E
FFA
Ch
肝
C
HDL
apoE
受体
B100
TG
C,PL
肝外组织
E
脂蛋白脂肪酶
apoC
apoE
FFA
B100
B100
L D L 受体
LPL
C
LDL
L D L 受体
溶酶体
HL
TG
C,PL
E
IDL
（V L D L 残粒）
肝外组织
甘油
CE
LDL Metabolism
核
LDL
HMGCoA
还原酶
LDL受体 溶酶体
ACAT
Ch
CE
氨基酸
LDL
结合
内吞
溶酶体
水解
游离
胆固醇
细胞膜
(－ )
(+)
(－ )
HMGCoA还原酶 (－ ) 胆固醇合成
ACAT
(Ch
CE)
LDL 受体 (－ ) LDL摄取
HDL Metabolism
合成胆汁酸
或从胆汁排出?
肝
小肠
Ch
pL
新生HDL
LDL
受体
HDL
受体
CE
LDL
LCAT
LCAT
CETP
CE
HDL2
CM 残粒
IDL
CE
PL
a p o AⅠ
a p o AⅡ
LPL
肝外组织
HDL3
apoC
apoE
CM
VLDL
Ch
组织
Ch
Function of plasma lipoproteins
• CM：Transport dietary from intestine to
liver (exogenous)
• VLDL: Transport lipids from liver to peripheral
tissues (endogenous
• LDL：endogenous Cholesterol transport
• HDL：reverse Cholesterol transport
Clinical importance for disease
Hypertriglyceridemia and CHD Risk:
Associated Abnormalities
Accumulation of chylomicron remnants
Accumulation of VLDL remnants
Generation of small, dense LDL
Association with low HDL
Increased coagulability
-  plasminogen activator inhibitor (PAI-1)
-  factor VIIc
- Activation of prothrombin to thrombin
Genetic Disease
•LPL Deficiency
•LDL receptor Deficiency
复习题
• 一、名词解释
1、血脂；2、血浆脂蛋白；3、载脂蛋白
• 二、问答
1、简述胆固醇的转化产物。
2、试述血浆脂蛋白的分类（电泳法、超
速离心法）、合成部位及功能。
选择题练习
脂代谢
1. 脂肪动员的限速酶是(
)
A 激素敏感性脂肪酶(HSL)
B 胰脂酶
C 脂蛋白脂肪酶
D 组织脂肪酶
E 辅脂酶
2.
下列不能促进脂肪动员的激素是(
A 胰高血糖素
B 肾上腺素
C ACTH
D 促甲状腺素
E 胰岛素
)
3. 下列物质在体内彻底氧化后,每克释放
能量最多的是(
)
A 葡萄糖
B 糖原
C 脂肪
D 胆固醇
E 蛋白质
4. 脂肪酸氧化分解的限速酶是(
A 脂酰CoA合成酶
B 肉碱脂酰转移酶I
C 肉碱脂酰转移酶II
D 脂酰CoA脱氢酶
E -羟脱氢酶
)
5. 脂肪酰进行-氧化的酶促反应顺序为(
A 脱氢,脱水,再脱氢,硫解
B 脱氢,加水,再脱氢,硫解
C 脱氢,再脱氢,加水, 硫解
D 硫解,脱氢,加水,再脱氢
E 缩合,还原,脱水,再还原
)
6. 严重饥饿时,脑组织的能量主要来源于(
A 糖的氧化
B 脂肪酸的氧化
C 氨基酸的氧化
D 乳酸氧化
E 酮体氧化
)
7. 通常生物膜中不存在的脂类是(
A 脑磷脂
B 卵磷脂
C 胆固醇
D 甘油三酯
E 糖脂
)
8. 下列关于HMG-CoA还原酶的叙述哪项事错误的(
A 此酶存在于细胞胞液中
B 是胆固醇合成过程中的限速酶
C 胰岛素可以诱导此酶合成
D 经磷酸化后活性可增强
E 胆固醇可反馈抑制其活性
)
9. 家族性高胆固醇血症纯合子的原发行代谢障碍是(
A 缺乏载脂蛋白B
B 由VLDL生成LDL增加
C 细胞膜LDL受体功能缺陷
D 肝脏HMG-CoA还原酶活性增加
E 脂酰胆固醇脂酰转移酶(ACAT)活性降低
)
10. 下列有关脂酸合成的叙述不正确的是(
)
A 脂肪酸合成酶系存在于胞液中
B 脂肪酸分子中全部碳原子来源于丙二酰CoA
C 生物素是辅助因子
D 消耗ATP
E 需要NADPH参与
11. The organ having the strongest ability of fatty
acid synthesis is ( )
A fatty tissue
B lacteal gland
C liver
D kidney
E brain
12. Which one transports cholesterol from
outer to inner of liver?
A CM
B VLDL
C LDL
D HDL
E IDL
13. Which one is essential fatty acid?
A palmitic acid
B stearic acid
C oleinic acid
D octadecadienoic acid
E eicosanoic acid
14. The main metabolic outlet of body cholesterol is (
A change into cholesterol ester
B change into vitamine D3
C change into bile acid
D change into steroid hormone
E change into dihydrocholesterol
)
15. 下列物质中与脂肪消化吸收有关的是(
A 胰脂酶
B 脂蛋白脂肪酶
C 激素敏感性脂肪酶
D 辅脂酶
E 胆酸
)
16. 合成甘油磷脂共同需要的原料有(
A 甘油
B 脂肪酸
C 胆碱
D 乙醇胺
E 磷酸盐
)
17. 参与血浆脂蛋白代谢的关键酶(
A 激素敏感性脂肪酶(HSL)
B 脂蛋白脂肪酶(LPL)
C 肝脂肪酶(HL)
D 卵磷脂胆固醇酰基转移酶(LCAT)
E 脂酰基胆固醇脂酰转移酶(ACAT)
)
18. 脂蛋白的结构是(
)
A 脂蛋白呈球状颗粒
B 脂蛋白具有亲水表面和疏水核心
C 载脂蛋白位于表面
D CM VLDL主要以甘油三酯为核心
E LDL HDL主要以胆固醇酯为核心
19. Which can be the source of acetyl CoA?
A glucose
B fatty acid
C ketone body
D cholesterol
E citric acid
20. The matters which join in synthesis of
cholesterol directly are ( )
A acetyl CoA
B malonyl CoA
C ATP
D NADH
E NADPH